5-aminooxadiazines



nited States Patent "cc 3,468,884

Patented Sept. 23, 1969 3,468,884 S-AMINUOXADIAZINES N Aldo J. Crovetti, Lake Forest, and Anne Mary Von Esch, North Chicago, 11]., assignors to Abbott Laboratories,

North Chicago, 111., a corporation of Illinois 5 O B No Drawing. Filed Aug. 15, 1966, Ser. No. 572,288 wherein Y is hydrogen or alkyl and Z is halogen; these lllt- C0711 99/ 9 A0111 9/28 compounds can readily be prepared by heating at or 250-444 11 Clalms above the melting point a compound of the formula Z ABSTRACT OF THE DISCLOSURE O:NC C-C=NOC( JIE[Y Compounds of the formula 0 NH; i) o The compound thus formed is then crystallized from a 15 suitable solvent such as ethanol, nitromethane, or aceto- U |L I nitrile. Alternatively, if desired, equimolar mounts of 5- NHR nitro-2-furylamidoxime, prepared by the method disclosed X N in US. Patent 3,097,214, issued July 9, 1963, and a comwherein X represents oxygen or sulfur, R represents hy- Pound of the formula drogen or alkyl and R represents hydrogen, methyl, or Z 0 acyl such as formyl, acetyl, propionyl, butyryl, valeryl, H, or benzoyl and which are useful antibacterial or antif l agents wherein Z, the halogen, is preferably chlorine or bromine,

and wherein each Z may be alike or dissimilar, may be re- 5 fluxed in an inert solvent such as toluene, xylene, dimethylformamide, or benzene in the presence of a hydrohalide This invention is concerned with compounds of the 2 formula acceptor such as pyridine, potassium carbonate, or tnethylamine or in acetic acid without acid acceptor to C--O N C-R form the intermediate compound designated in Formula g. g I C above in situ and without actually isolating said intermediate contmumg the reaction at reflux temperature to X N A close the ring. The reaction mixture is then concentrated and the method for their preparation. In this and succeedand the residue recrystallized to obtain the desired oxaing formulas, X represents oxygen or sulfur, R represents diazole as a crystalline solid.

hydrogen or alkyl and R represents hydrogen, methyl, or The aminooxadiazine compounds of the present invenacyl such as formyl, acetyl, propionyl, butyryl, valeryl, tion wherein X is sulfur can be prepared by suspending or benzoyl. The term alkyl includes the straight and 5-nitro-2-thiophene carboxamidoxime, prepared by the branched alkyl radicals containing from one to sixteen method of Bercot-Vatteroni, Ann. Chim., 7, 303-307,

carbon atoms, inclusively. 1962, in chloracetylchloride. The mixture is then heated These novel compounds are active antibacterial and at reflux and the excess acid chloride removed by distillaantifungal agents, and have been found to be active agents tion. A solvent such as n-butanol is added, and the mixagainst T riclzomonas vaginalis and foetus in vitro and have ture is refluxed overnight after which it is filtered and also shown in vivo activity in mice against T. vaginalis o1 cooled, The 5 chloromethyl-3-(5-nitro-2-thienyl-l,2,4- E. 0011'. The compounds may be dispersed in an inert oxadiazole which crystallizes is then treated with amsolid or in a liquid and applied as a dust or spray. In a monia to obtain the aminooxadiazine. To prepare the acyl typical application, the compound of Formula A, Wherecompounds, the aminooxadiazine is acylated With an acyl in X was oxygen, R was hydrogen and R was acetyl, inanhydride. hibited the growth of the above-named organisms when The invention is further illustrated by the following p y as an aqueous omposition in a concentration examples which describe the specific processes used to of 25 parts per million. prepare representative compounds.

The compounds of the present invention wherein X is oxygen are prepared by the reaction of a haloalkyloxadiazole (the preparation of which will hereinafter be de- Example l.5-amino-3-(5-nitro2-furyl)- 6H1,2,4-oxadiazine scribed in detail) with ammonia or methylamine in a 15 g. of 3-(5-nitro-2-furyl)-5-chloromethyl-1,2,4-oxadisuitable polar solvent such as ammonia, dimethylformaazole was suspended in 100 ml. liquid ammonia precooled mide, dimethylacetamide, 1,2-dimethoxyethane, or aroto 65 C. (by use of acetone-Dry Ice bath), and stirred at matic solvents such as benzene and toluene. The reaction this temperature for two hours. The suspension was then is conducted at temperatures ranging between 65 C. allowed to slowly reach the temperature of liquid amand 25 C. The solution is then filtered to separate the monia. The resultant compound was filtered, dried, and

aminooxadiazine product. To prepare the acyl comthen washed thoroughly with water. A yield of 90% of pounds, the aminooxadiazine, prepared as previously dethe bright yellow compound (M.P. 220222 C. (dec.))

scribed, is acylated with an acyl anhydride acting as a was obtained. This material is of satisfactory purity for chemical reagent or as a solvent, or, alternatively, in pyrimost uses. However, if recrystallization is desired, the dine. The reaction is conducted at from 40 C. to 90 C: dried product can be crystallized from nitromethane, difor 1 to 36 hours. The reaction mixture is then decommethylformamide and Water or methyl Cellosolve and posed in ice water and the final product is isolated by filtrawater.

tion. The product may be purified from suitable organic solvents such as, for example, ethyl alcohol, nitromethane, dimethylformamide and water, methyl Cellosolve, and dimethylsulfoxide and water. '10 A suspension of 4.5 g. of 3-(5-nitro-2-furyl)-5-a-bromo- Referring now to the haloalkyloxadiazole starting mae y1-1,2, adiaZ 1e n 25 ml. of liquid ammonia Was terials which can be depicted by the formula made (no external cooling) and stirred. The ammonia Example 2.-5-amino-3-(5-nitro-2-furyl)-6-methyl 1,2,4-oxadiazine was allowed to evaporate. When the ammonia completely disappeared, the residue was washed with water to remove ammonium bromide. The residue was then dried and recrystallized from boiling nitromethane. The compound is a bright yellow solid melting at 270 C. (dec.).

Example 3 -methylamino-3- 5 -nitro-2-furyl 6H-1,2,4-oxadiazine A suspension of 18.4 g. of 3-(5-nitro2-furyl)-5-chloromethyl-1,2,4-oxadiazole in 100 m1. of benzene was made. 2 ml. of dimethylformamide and 5.0 g. of methyl amine were added. The preparation was then shaken in a closed container at room temperature overnight.

The solution was subsequently filtered, yielding a brown solid. Recrystallization with ethanol as the solvent yielded 1.0 g. of a yellow solid, M.P. 222224 C.

Example 4.5-butyramido-3 5-nitro-2-fury1) 6H- 1 ,2,4-oxadiazine To a solution of 4.2 g. of 5-amino-3-(5-nitro-2-furyl)- 6H-1,2,4-oxadiazine in 25 ml. of pyridine was added 5.0 ml. of butyric anhydride. The preparation was then heated at 55 C. for 24 hours, after which it was poured on ice. A cream-colored solid precipitated out, yielding 3.4 g. of the desired product, M.P. 158161 C. (dec.).

Example 5.5-chloromethyl-3-(5-nitro-2-thienyl 1,2,4-oxadiazole gm. of 5-nitro-2-thiophene carboxamidoxime was suspended in 30 ml. of chloroacetylchloride. The suspension was heated at reflux for two hours, and the excess acid chloride was then removed by distillation. Added and refluxed overnight was ml. of n-butanol. The solution was then filtered and cooled, and the product crystallized out. M.P. 72-74 C.

Analysis.Calculated for C H CIN O S: C, 34.24%; H, 1.64%; N, 17.11%. Found: C, 33.93%; H, 1.75%; N, 17.28%.

Example 6.5-amino-3-(5-nitro-2-thienyl)- 6H-1,2,4-oxadiazine A suspension of 2.0 g. of 5-chloromethyl-3-(S-nitro-Z- thienyl)-1,2,4-oxadiazole in 5 ml. of liquid ammonia was made. The liquid ammonia evaporated, leaving a green residue. The residue was water washed, dried, and recrystallized from boiling nitromethane. The product obtained had a melting point of 228230 C. (dec.) and was a brilliant yellow.

Analysis.Calculated for C7H6N4O3SI C, 37.16%; H. 2.67%; N, 24.77%. Found: C, 37.18%; H, 2.69%; N. 24.79%.

Example 7.-5 -acetamido-3- 5 -nitro-2-thienyl 6H-1,2,4-oxadiazine OXADIAZIN E S Analyses Calculated Found Solvents For Ex. R R M.P. Recrystallization C H N C H N H 220222 C. (deo) Nitromethane C7H6N1O4 40. 00 2. 88 26. 66 40. 05 2 93 26. 82 CH; 220224 C. (dee) Ethanol C8HN404 42. 86 3. 60 24. 99 42. 78 3. 60 24. 87 H "0 C. ((190.) Nitromethane CgHgN O4 42. 86 3. 60 24. 99 42. 81 3. 61 24. 84 H 225227 C. (180.) Ethyl Acetate. C H N O 45. 38 4. 23 23. 52 45. 53 4. 24 23. 58

1.1 198200 C. (doe) 12A. Ethanol (31 111 15140 47. 62 4. S0 22. 21 47 4. 99 2. 41

11 2l2214 C. (doe) Nitromethaue C1UH12N404 47. 62 4. 8O 22. 21 47. 77 4. 94 2:2. 18 H 1863-188: C. ((180.) do C 1H N4O 49. 62 5. 30 21. 04 49. 80 5. 40 20. 75 II 156 -160 C. ((180. do C17H26N4O4 58. 26 7. 48 15. 99 58. 26 7. 57 16. 00 II 143 -145 C. (dec. (10 C21H34N404 62. 04 8. 43 13. 78 96. 29 8. 60 13. 82 H 138 140 C. (deo) d0 C2aH3sN404 63. 56 8. S2 12. 89 63.89 8. 78 12. 87

0') 1S H CH 182-1S4 C. ((100.) 3A Ethanol CsHeN4O5 40. 43 2. 54 23. 53 40. 30 2. 64 23. 44

(H) 19 H -C 011 JCT-204 C. (dec.) l0 CaHsN4O5 42. 86 3. 20 22. 22 43. 3. 30 56 T? 20"... 11 -0 011 011 195197 O. (dcen) do ChullwNiOr. 45. 11 3. 79 21. 05 45.16 3. 51 21. 06

(III) 1 H --C 011:)20113 158-1G1 C. (dCC.) -1l0 011111114405 47.14 4. 32 19. 99 47. 07 4.15 19.87

[I a 0 2a 11 C CHZ)3CI'I3 123 C. (deo) d0 C12H14N;O5 48. 9S 4. 80 19.04 48. 73 4. 72 19. 08

ll 23"... H U 21021l C. (dec.) d0 OHH1QN4O5 53.51 3. 21 17. 83 53. 30 3.24 17. 86

24..." --CH3 -CCH 171173 O. (dec.) .....(10 CmHwN4O5 45.11 3. 79 21.05 45.07 3. 65 21. 00

fl) 25... Cl[; 6011 011; 171174" 0. (due). ......(10 C1 1I12N-105 47.14 4. 32 19. 99 47.17 4.31 19. 51

f) 26..." OH CH CCH 142 C. (dec.)-. d0 C11II gN4O5 47.14 4. 32 19.99 47. 22 4. 64 19.93

While the invention has been illustrated by the foregoing examples, it will be apparent that various equivalent changes and modifications may be resorted to without departing from the spirit and scope thereof, and it is understood that such equivalent embodiments are intended to be included herein.

What is claimed is:

1. A compound of the formula wherein X is selected from the group consisting of oxygen and sulfur; R is selected from the grou consisting of hydrogen and alkyl of from 1 to 16 carbon atoms; and R is selected from the group consisting of hydrogen, methyl, and lower alkanoyl or benzoyl.

2. A compound as claimed in claim 1 wherein X is oxygen,

3. A compound as claimed in claim 1 wherein X is sulfur.

1-. A compound as claimed in claim 2 wherein R is hydrogen and R is hydrogen.

5. A compound as claimed in claim 2 wherein R is hydrogen and R is methyl.

6. A compound as claimed in claim 2 wherein R is hydrogen and R is acetyl.

7. A compound as claimed in claim 2 wherein R is hydrogen and R is propionyl.

8. A compound as claimed in claim 3 wherein R is hydrogen and R is hydrogen.

9. A compound as claimed in claim 3 hydrogen and R is acetyl.

10. A method for the preparation of a compound of the formula wherein R is wherein X is selected from the group consisting of oxygen and sulfur; R is selected from the group consisting of hydrogen and alkyl of from 1 to 16 carbon atoms; and R is selected from the group consisting of hydrogen, methyl, and lower alkanoyl or benzoyl; which comprises reacting a compound of the formula Wt ll il ll wherein X is selected from the group consisting of oxygen and sulfur, R is selected from the group consisting of hydrogen and alkyl of from 1 to 16 carbon atoms, and R is selected from the group consisting of hydrogen and methyl, which comprises reacting a compound of the formula ll OzN-C N wherein X is as above indicated, Y is selected from the group consisting of hydrogen and alkyl of from 1 to 16 carbon atoms and Z is halogen, with an amination agent selected from the group consisting of ammonia and methylamine in a solvent selected from the grou consisting of polar compounds and aromatic compounds.

References Cited UNITED STATES PATENTS 3,397,201 8/1968 Trepanier 260244 HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner US. Cl. X.R. 424248 

